SUMMARY:The presence of lymph node metastases is the major determinant for prognosis in head and neck squamous cell carcinoma (HNSCC). It is at present unknown whether the same holds true for the presence of histologically undetectable micrometastases. We analyzed 456 histologically tumor-negative lymph nodes of 23 HNSCC patients without (pN0) and 18 patients with one or two tumor-positive lymph nodes (pNϩ) in their neck dissection specimens at histopathologic examination. To detect the presence of disseminated tumor cells and micrometastases in these lymph nodes, we used real-time quantitative RT-PCR with E48 (Ly-6D) transcripts as a squamous cell-specific molecular marker. The results were compared with histopathologic examination and clinical outcome. E48 transcripts were detected in lymph nodes of 5 (22%) of 23 patients in the pN0 group, and in histologically negative lymph nodes of 10 (56%) of 18 patients in the pNϩ group. In the pN0 group, the presence of E48-positive lymph nodes was significantly associated with a distinctly poor cause-specific survival as compared with those with E48-negative lymph nodes. Our results indicate that E48 real-time quantitative RT-PCR is a suitable method for the detection of micrometastases in lymph nodes of patients with HNSCC. Moreover, detection of micrometastases seems clinically relevant but should be confirmed in a large multicenter trial. (Lab Invest 2003, 83:1233-1240. Head and neck squamous cell carcinoma (HNSCC) accounts for 5% of all newly diagnosed cancers in the Western world (Muir and Weiland, 1995). Dissemination to lymph nodes in the neck is one of the most important prognosticators for HNSCC. Only 7% of patients without lymph node metastases develop distant metastases, whereas this occurs in 50% of patients with more than three tumor-positive lymph nodes (Leemans et al, 1993). Moreover, when tumor is diagnosed in the regional lymph nodes, the neck should be treated. The clinical management is further determined by the number of tumor-containing lymph nodes, the involved level(s) in the neck, and the presence of extranodal spread. Therefore, accurate assessment of the regional lymph nodes for metastases is of crucial importance. However, classical diagnostic modalities, such as radiologic and histopathologic examination are of limited sensitivity to detect small numbers of tumor cells.Recently, molecular techniques have been applied in a number of studies to detect the presence of micrometastases that are missed at routine histologic examination for the early diagnosis of cancer (Brennan et

Our study seems to validate the SN hypothesis for oral and oropharyngeal cancer. The role of SN biopsy in the management of the N0 neck in such patients has yet to be established through prospective trials. SN identification (and thus biopsy) does not seem to be reliable in patients with tumors located in or close to the midline.

The uncertainty of prognosis and possibility of local recurrence of paragangliomas even after a long period emphasizes the importance of wide local surgical resection with or without adjuvant therapy and makes long-term follow-up and continued surveillance of the patient mandatory.

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Activated CTLs and NK cells induce apoptosis via multiple mechanisms, including that termed granule exocytosis. The latter pathway consists of vectorial secretion of perforin and a family of granule-associated serine proteases (granzymes) to the target cell. To establish whether granzymes are released extracellularly during cytolytic reactions in vivo, ELISAs that measure the native enzymes were developed and were found to specifically detect granzyme A (GrA) and granzyme B (GrB) at picogram concentrations. Low levels of GrA and GrB were present in plasma of healthy individuals (GrA, 33.5 pg/ml (median); GrB, 11.5 pg/ml (median)), whereas significantly higher levels were present in patients with ongoing CTL response, i.e., patients suffering from infections by EBV or HIV type 1. Markedly elevated levels were also noted in synovial fluid of patients with active rheumatoid arthritis. The measurement of soluble granzymes should be useful to assess clinical disorders associated with activated CTL and NK cells. Furthermore, these results suggest that granzymes mediate biologic effects beyond their described role in apoptotic cell death.